Arias-Badia Marcel, Pai Chien-Chun Steven, Lwin Yee May, Chen PeiXi, Srinath Aahir, Tanaka Miho, Musser Emily, Goodearl Andrew, Gorman Jacob V, Ritacco Wendy, Fong Lawrence
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
J Immunother Cancer. 2025 Apr 2;13(4):e010566. doi: 10.1136/jitc-2024-010566.
Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.
We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.
Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic "non-exhausted" antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.
These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases.
免疫检查点阻断（ICB）可诱导抗肿瘤疗效，但也会引发免疫相关不良事件。全身给药的ICB可激活宿主全身的免疫细胞。具有蛋白水解切割掩蔽结构域的条件性激活ICB可能会减少抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抗体所见的不良事件。
我们研究了结合CTLA-4和肿瘤相关抗原前列腺干细胞抗原（PSCA）的条件性激活双可变域IgG（DVD）的不同形式如何在同基因皮下和转移性小鼠肿瘤模型中产生疗效。我们还通过多参数流式细胞术确定了这些DVD调节免疫反应的能力。
条件性激活的DVD可将抗肿瘤疗效与毒性分离。一种可从靶肿瘤细胞释放的完全可切割构建体（对称DVD，sDVD）与保留肿瘤抗原结合的不对称DVD相比，显示出更高的抗肿瘤疗效。sDVD在肿瘤和肿瘤引流淋巴结中引发了检测到的最高肿瘤抗原特异性T细胞反应，同时肿瘤内和脾脏中“未耗竭”抗原特异性CD8 T细胞的比例也最高。sDVD还诱导了最高程度的T细胞记忆和自我更新潜力。这些效应取决于肿瘤的PSCA表达。
这些发现支持这样一种观点，即ICB对远离肿瘤细胞的抗肿瘤免疫的调节对于最佳抗肿瘤免疫至关重要。双特异性sDVD抗体设计可能比传统ICB在原发性肿瘤和转移瘤中都能实现更好的全身抗肿瘤反应。
